A method for synthesizing nucleoside analogs in a continuous flow reactor

Abstract

The invention discloses a method for synthesizing nucleoside analogs in a continuous flow reactor, the method comprising the following steps: using (2R, 3R, 4R, 5R)-2-(4-aminopyrrole [1,2-f] [1,2,4]triazin-7-yl)-3,4-dibenzyloxy-5-((benzyloxy)methyl)tetrahydrofuran-2-nitrile dichloromethane solution as raw material solution, with The dichloromethane solution of boron trichloride is the auxiliary material liquid for the debenzylation reaction. The two material liquids enter the mixer through their respective pump systems, then flow through the main reaction pipeline, and then enter the aqueous alkali solution to quench, filter, and beat. That is, the target product (2R, 3R, 4S, 5R)-2-(4-aminopyrrole[1,2-f][1,2,4]triazine-7-yl)-3,4-dihydroxy- 5‑(Hydroxymethyl)tetrahydrofuran‑2‑carbonitrile. The method of the invention has the advantages of simple operation, high efficiency, high product yield and high purity, and is suitable for large-scale production.

Description

Technical field: [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing nucleoside analogs using a continuous flow reactor. Background technique: [0002] Compound (2R, 3R, 4S, 5R)-2-(4-aminopyrrole[1,2-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-( Hydroxymethyl)tetrahydrofuran-2-carbonitrile is a nucleoside analog, code name GS-441524, which mainly targets viral RNA polymerase and interferes with the process of viral RNA transcription / replication. GS-441524 is phosphorylated into active triphosphate metabolites (NTP structural analogs) by cellular kinases in cells. In viral RNA synthesis, active NTP structural analogs act as competitors of natural nucleoside triphosphates and natural nucleosides (NTP) competes to participate in the transcription / replication of RNA. When the transcription / replication product is inserted into the GS-441524 molecule, the transcription / replication will be terminated prematurely, thereby ...

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Problems solved by technology

The temperature control operation is too complicated and cumbersome for operators, and there are potential safety hazards

[0007] (3) The operation process, the post-treatment process is complex, resulting in a certain fluctuation in the yield of the product (65-75%), so there is still a large room for improvement in the yield

In terms of the reaction process, on the one hand, there is an incomplete phenomenon in the removal of the hydroxyl protecting group, and the incomplete removal of the hydroxyl protecting group will produce a series of impurities; on the other hand, one of the by-products, benzyl chloride, is In the quenching operation process, because the quenching time is too long, the substitution of benzyl chloride and the amino group of the nitrogen heterocycle will occur, and N-benzyl substitution impurities will be generated; the impurity types in the above two aspects will be precipitated together with the product; based on Due to the special solubility properties of the product (difficult to dissolve in general organic solvents) and the similarity between the above-mentioned series of impurities and the solubility of the product, it is very difficult to develop a recrystallization purification process, so the purity of the product is still greatly improved space

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